DNA2 drives processing and restart of reversed replication forks in human cells |
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| Authors: | Saravanabhavan Thangavel Matteo Berti Maryna Levikova Cosimo Pinto Shivasankari Gomathinayagam Marko Vujanovic Ralph Zellweger Hayley Moore Eu Han Lee Eric A Hendrickson Petr Cejka Sheila Stewart Massimo Lopes Alessandro Vindigni |
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| Institution: | 1.Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104;2.Institute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland;3.Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;4.Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455 |
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| Abstract: | Accurate processing of stalled or damaged DNA replication forks is paramount to genomic integrity and recent work points to replication fork reversal and restart as a central mechanism to ensuring high-fidelity DNA replication. Here, we identify a novel DNA2- and WRN-dependent mechanism of reversed replication fork processing and restart after prolonged genotoxic stress. The human DNA2 nuclease and WRN ATPase activities functionally interact to degrade reversed replication forks with a 5′-to-3′ polarity and promote replication restart, thus preventing aberrant processing of unresolved replication intermediates. Unexpectedly, EXO1, MRE11, and CtIP are not involved in the same mechanism of reversed fork processing, whereas human RECQ1 limits DNA2 activity by preventing extensive nascent strand degradation. RAD51 depletion antagonizes this mechanism, presumably by preventing reversed fork formation. These studies define a new mechanism for maintaining genome integrity tightly controlled by specific nucleolytic activities and central homologous recombination factors. |
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